Guide to Managing Hepatitis C With Pegylated Interferons - CECity

This Special Report was
supported by an
educational grant from
Schering Hepatitis
Innovations
BROUGHT TO YOU BY THE PUBLISHER OF
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FACULTY
Ira M. Jacobson, MD
Vincent Astor Professor of Clinical
Medicine
Chief, Division of Gastroenterology
and Hepatology
Weill Medical College of Cornell
University
NewYork Presbyterian Hospital
(Weill Cornell campus)
New York, New York
Dr. Jacobson is on the speaker’s
bureau for Gilead Sciences and
Schering-Plough, and is a consultant
for Akros Pharma, Amgen, Centocor,
InterMune, Ortho Biotech, Prometheus
Laboratories, Schering-Plough, and
Valeant Pharmaceuticals. He has
received grants/research support from
InterMune, Isis Pharmaceuticals,
Prometheus Laboratories, Ribozyme
Pharmaceuticals, and Schering-Plough.
F. Fred Poordad, MD
Assistant Professor of Medicine
UCLA School of Medicine
Associate Director, Hepatology and
Liver Transplantation
Cedars-Sinai Medical Center
Los Angeles, California
Dr. Poordad is on the speaker’s
bureau for Ortho Biotech, Roche
Pharmaceuticals, and Schering-Plough,
and is a consultant for Schering-
Plough, Salix, and Prometheus Laboratories.
He has received grants/research
support from Ribapharm, Roche
Pharmaceuticals, and Schering-Plough.
Jointly sponsored by the
University of Kentucky
and McMahon
Publishing Group
Guide to Managing Hepatitis C
With Pegylated Interferons
NEEDS STATEMENT
A CCREDITATION AND DESIG-
NATION STATEMENTS
This activity has been planned and implemented
in accordance with the Essential Areas and policies
of the Accreditation Council for Continuing Medical
Education (ACCME) through the joint sponsorship of
the University of Kentucky College of Medicine and
McMahon Publishing Group. The University of Kentucky
College of Medicine is accredited by the
ACCME to provide continuing medical education for
physicians.
The University of Kentucky College of Medicine
designates this educational activity for a maximum of
1 category 1 credit toward the AMA Physician’s
Recognition Award. Each physician should claim
only those hours of credit actually spent in the educational
activity.
TARGET AUDIENCE
This educational program is intended for gastroenterologists.
LEARNING OBJECTIVES
After completing this educational activity, the participant
should be able to:
1 Describe the goals of peginterferon–ribavirin therapy
for HCV infection.
2 Define early virologic response, sustained virologic
response, and the best predictor of sustain virologic
response, as related to peginterferon–
ribavirin combination treatment for patients with
HCV infection.
3 Review clinical and patient factors that make a difference
in individualizing patient care and that
influence therapeutic outcomes.
CME CERTIFIED APRIL 2004
Combination therapy with pegylated interferon
and ribavirin enables clinicians to cure many
patients infected with the hepatitis C virus (HCV)
who may have otherwise progressed from an HCV
infection to cirrhosis and, subsequently, hepatocellular
carcinoma. Yet, because many factors influence
efficacy and therapeutic outcomes, clinicians
must educate themselves with regard to the use of
this combination therapy in order target therapy
toward patients most likely to obtain benefit from it.
METHOD OF PARTICIPATION
This activity should take approximately 1 hour to
complete. The participant should, in order, read the
objectives and monograph, answer the multiplechoice
post-test, and complete the answer form, registration,
and evaluation on page 8. This credit is valid
through April 30, 2005.
DISCLOSURE OF UNLABELED
USE
This educational activity contains discussion of
published and/or investigational uses of peginterferon;
some uses of these agents have not been
approved by the Food and Drug Administration.
Please refer to the official prescribing information for
each product for discussion of approved indications,
contraindications, and warnings.
DISCLOSURE OF FINANCIAL
INTEREST
All faculty members participating in continuing
medical education programs sponsored by the University
of Kentucky Colleges of Pharmacy and Medicine
Continuing Education Office are expected to
disclose any real or perceived conflict of interest related
to the content of their presentations. Faculty disclosures
are included herein.
The University of Kentucky College of Medicine
presents this activity for educational purposes
only. Participants are expected to use their own
expertise and judgment while engaged in the practice
of medicine. The content of this educational
activity is provided solely by the faculty, who have
been selected because of recognized expertise in
the field.
Release Date: April 2004 Expiration Date: April 30, 2005

Introduction
Recent therapeutic advances in the management of patients
with hepatitis C virus (HCV) infection have raised the bar for
expected outcomes. The best example of this has been the use
of pegylated interferons. The majority of patients infected with
HCV who have been treated with a combination of peginterferon
and ribavirin have had sustained virologic response (SVR).
With increasing experience indicating the rarity of virologic
relapse in patients with SVR, clinicians are now able to include
“cure of infection” among the goals of treatment. 1,2 While the
National Institutes of Health’s Consensus Development Conference
Statement on the Management of Hepatitis C suggests
that all patients with hepatitis C could be considered as potential
candidates for this therapy, 3 many patients infected with
HCV represent complicated cases that require individualized
attention with tailored dosing, careful monitoring, and management
of side effects. Therefore, clinicians need to consider individual
patient characteristics to target therapy toward those at
greatest risk of progressive liver disease, with diligent attention
to maximizing its tolerability.
Maximizing Therapeutic Outcomes
Ira M. Jacobson, MD
Vincent Astor Professor of Clinical Medicine
Chief, Division of Gastroenterology and Hepatology
Weill Medical College of Cornell University
NewYork Presbyterian Hospital (Weill Cornell campus)
New York, New York
Target Patient Population
To maximize the benefits of peginterferon–ribavirin combination
therapy, clinicians need to evaluate each candidate for
symptoms, degree of liver disease, risk of future progression,
likelihood of response to therapy, and likelihood of tolerating
therapy. Liver biopsy continues to play a major role in patient
evaluation, although there is increasing interest in serum fibrosis
assays and further data are awaited. Patients with HCV who
are at particular risk of progressive fibrosis include those who
Table 1. Key Definitions Used in Clinical Studies 7
Negative predictive value: the chance of nonresponse
to antiviral therapy in patients who have not achieved
an early virologic response (EVR) by 12 weeks of
treatment.
Positive predictive value: the chance of achieving a
sustained virologic response (SVR) in patients who
have achieved an EVR.
are over 40 years of age at the time of infection, and have a history
of alcoholism, persistently elevated levels of alanine
transaminase (ALT) and aspartate transaminase (AST), coinfection
with HIV, and a significant degree of necroinflammatory
activity and fibrosis on liver biopsy. In addition, males and those
patients with a body mass index >25 kg/m 2 appear to have an
enhanced risk of progressive fibrosis. 4-6
Many hepatologists recommend liver biopsy even in patients
whose liver enzyme levels are normal, because some such
patients still have significant liver injury. Thus, the liver biopsy
specimen can provide crucial information to help the clinician
and the patient move to the next step. If the biopsy specimen indicates
more than minimal fibrosis, then the patient should be treated.
Even patients with minimal fibrosis should be informed of the
option of treatment, since some of them may wish to attempt to
eradicate their infection. Some hepatologists currently question
the need for biopsy in selected patients, such as those with HCV
genotype 2 or 3 and no evidence of cirrhosis, because therapy
offers such a high chance of cure (80%). When therapy is decided
upon, the duration of treatment is determined by the patient’s
HCV genotype: for example, 24 weeks of therapy for HCV genotypes
2 and 3, and 48 weeks for HCV genotype 1.
Role of Early Virologic Response
Once antiviral therapy has been started, the treating clinician
can predict the chance of a patient achieving an SVR. Recently
Table 2. Early Virologic Response (EVR) and Treatment Outcome:
Peginterferon alfa-2b 1.5 mcg/kg + ribavirin 800 mg/d
Viral Load Week EVR NPV PPV
PCR neg 4 29% 59% 89%
≥3 log10 drop 4 51% 75% 82%
≥2 log10 drop 4 63% 87% 78%
≥1 log10 drop 4 74% 95% 70%
PCR neg 12 60% 91% 84%
≥3 log10 drop 12 70% 95% 75%
≥2 log10 drop 12 74% 100% 72%
≥1 log10 drop 12 82% 100% 66%
PCR neg 24 64% 99% 81%
— — EVR Total % NR/No EVR %SVR/EVR
2
EVR, early virologic response; NPV, negative predictive value; NR, no response; PPV, positive predictive value; PCR neg, polymerase chain reaction negativity;
SVR, sustained virologic response.
Based on Hepatology 2003;38:645-652.

published data support the use of early virologic response
(EVR) measurements as a means of predicting which patients
will achieve SVR.
This was the conclusion of data analysis from the trial by
Manns et al, 1 which studied the combination of peginterferon
alfa-2b and ribavirin. Davis et al evaluated EVR rates at 4, 12,
and 24 weeks of therapy. The goal of the study was to help
clinicians decide which HCV patients would benefit most from
continued therapy, and to avoid the continuation of treatment in
as many nonresponders as possible without depriving patients
who might still have a realistic chance of SVR.
The authors found that the time point that provided the greatest
positive predictive value and negative predictive value for
SVR among the definitions of EVR was ≥2 log10, or a hundredfold
drop in viral load at 12 weeks of therapy (Tables 1 and 2). 7
A ≥2 log10 drop in viral load at 12 weeks provided a 72% positive
predictive value and a 100% negative predictive value. If a
patient achieved an EVR at 12 weeks of therapy, there was a
72% chance of achieving an SVR at the end of therapy. However,
if a patient failed to achieve an EVR, the likelihood of a subsequent
SVR during the trial was zero—there were no patients
who achieved SVR among those who did not have a ≥2 log10
drop at 12 weeks of therapy.
Looking at the specific patient numbers, Davis et al 7 found
that 380 of the 511 patients (74%) treated with 1.5 mcg/kg of
peginterferon alfa-2b weekly plus 800 mg per day of ribavirin
during the trial achieved an EVR (defined as ≥2 log10 drop in
viral load at 12 weeks); again, the majority of patients (72%)
went on to achieve an SVR. In contrast, none of the 131 patients
who failed to achieve an EVR at 12 weeks achieved an SVR.
In another trial, by Fried et al, 2 which studied the combination
of peginterferon alfa-2a and ribavirin, 86% of patients treated
with 180 mcg peginterferon alfa-2a once weekly plus 1,000 mg
or 1,200 mg per day ribavirin (depending on body weight)
achieved an EVR, which was defined as ≥2 log10 drop in viral
load at 12 weeks. 8 In the Fried study, the positive predictive
value was 65% (ie, 65% of those who achieved optimal EVR at
12 weeks went on to achieve an SVR). The negative predictive
value was approximately 97% (ie, 3% of those who did not
achieve EVR at 12 weeks went on to achieve an SVR).
When one is considering whether or not to terminate therapy
based on EVR, these analyses support the 12-week time point
as the best time to use in clinical practice. If a patient has mild
fibrosis and virologic eradication is the sole goal of therapy,
stopping therapy can be considered appropriate at that time
point in light of these data.
Importance of Adherence
Because of the significance of obtaining an EVR, clinicians
need to educate patients about the importance of adhering to
their therapeutic regimen, particularly during the initial 12-
week period.
Using the Manns et al trial data, 1 Davis et al found that if a
patient took ≥80% of the peginterferon dose and ≥80% of the
ribavirin dose during the first 12 weeks of therapy, the patient’s
response rate was optimal. 7 However, if the patient took

On the basis of this analysis, some clinicians would recommend
continuing therapy beyond the 12-week time point, for as
long as 6 to 12 months, in patients with advanced fibrosis who
have failed to achieve an EVR, as defined by ≥2 log10 drop in
viral load, to potentially maximize the histologic benefit.
Maintenance Therapy
There are ongoing investigations that take this concept a
step further—continuing therapy beyond the 12-month treatment
period in a maintenance form of therapy. The rationale behind
this approach is that if 6 to 12 months of treatment can reduce
inflammation and fibrosis, perhaps further treatment would provide
further benefit. To date, the only published prospective trial
on maintenance therapy has indicated a significant reduction in
inflammatory scores and a trend toward less fibrosis. 12 Currently,
there are 3 ongoing studies exploring maintenance therapy—
HALT-C (Hepatitis C Antiviral Long-Term Treatment Against
Cirrhosis), which is evaluating peginterferon alfa-2a plus ribavirin,
COPILOT (Colchicine Versus PEG-Intron Long-Term),
and EPIC (Evaluation of PEG-Intron in Chronic Hepatitis C Cirrhosis).
The latter 2 studies are evaluating peginterferon alfa-2b;
all 3 of the maintenance trials are evaluating lower dosing regimens.
Nezam H. Afdhal, MD, presented preliminary data from
the COPILOT trial at the 2002 American Association for the
Study of Liver Diseases meeting, which indicated the possible
beginning of a trend toward fewer significant clinical events in
patients treated with peginterferon alfa-2b, given at a dose of
0.5 mcg/kg once weekly, than in those treated with colchicine
0.6 mg twice daily. 13 Further data are awaited.
Treatment Algorithm
All patients infected with HCV and treated with peginterferon–ribavirin
combination therapy should be evaluated for success
of therapy based on the optimal EVR at 12 weeks (Figure
2). If a patient has a ≥2 log10 drop in HCV RNA, or HCV RNA is
undetectable, treatment should be continued. The continuation
of treatment beyond 24 weeks is determined based on the
patient’s genotype: HCV genotype 1 patients should continue
therapy for 48 weeks if HCV RNA is negative; if HCV RNA is still
positive at week 24, cessation of therapy should be considered.
Generally, HCV genotype 2 and 3 patients should stop therapy
at 24 weeks if HCV RNA is negative. One possible exception to
this rule might be patients with cirrhosis, but this is a controversial
issue. Patients with METAVIR scores of F3 or F4 beyond 12
weeks, even if no EVR was demonstrated, might be treated
longer to accrue additional histologic benefit. Similarly, patients
defined as late responders might benefit from treatment for
more than a year; but this is unproven. At the end of treatment
in responders, qualitative testing, with either PCR or transcription
mediated amplification (TMA), should be performed. Testing
should be repeated 6 months later to assess patient
outcome.
Conclusion
To maximize the benefits of peginterferon–ribavirin combination
therapy in the HCV-infected patient, clinicians should first
educate the patient on the importance of adhering to the therapeutic
regimen, and then measure the patient’s EVR at the 12-
week time point. The EVR rate can reliably predict therapeutic
outcomes and can serve as the basis for avoiding unnecessary
continuation of therapy in those patients least likely to benefit
from it. There is some preliminary evidence 12,13 that prolonging
therapy in selected patients, or placing patients on maintenance
therapy, may be considered to reduce inflammation and,
potentially, prevent progression of fibrosis. At least 3 multicenter
studies on maintenance therapy with peginterferon are in
progress. The concept of prolonging therapy beyond 48 weeks
in late responders, prior nonresponders, or prior relapsers
requires additional evaluation.
Week 12:
Quantitative HCV RNA testing (determine EVR)

Patient Management Issues
F. Fred Poordad, MD
Assistant Professor of Medicine
UCLA School of Medicine
Associate Director, Hepatology and Liver Transplantation
Cedars-Sinai Medical Center
Los Angeles, California
To maximize the likelihood of achieving an SVR in patients
infected with HCV taking peginterferon–ribavirin combination
therapy, clinicians need to carefully monitor for and treat disease
complications and medication side effects that might
hamper treatment success. Such complications and side
effects can lead to decreased adherence to the therapeutic regimen—dose
reductions and premature discontinuation of therapy
(Table 3). 1,2 This decreased adherence to the treatment
regimen, in turn, lessens the efficacy of therapy and the likelihood
of achieving an SVR. 1,14,15 Following is an overview of
some of the more common side effects of interferon therapy
and treatment options.
Table 3. The Frequency of Therapeutic Adjustments
In Patients Treated With Peginterferon and
Ribavirin
Peginterferon
alfa-2a Plus
Ribavirin (%)
Dose Modifications 32 42
Premature
Discontinuation
10 14
Adverse Events 7 12
Laboratory
Abnormalities
3 2
Peginterferon
alfa-2b Plus
Ribavirin (%)
Based on Lancet 2001;358:959-965 and N Engl J Med 2002;347:975-982.
Depression
Depression is a significant comorbid factor to consider when
treating HCV-infected patients. Depression is uncovered in one
third of patients at the time of diagnosis of HCV infection. 14 The
reasons for the high rate of depression in this population may in
part be related to fatigue or patients’ concerns about their
future health. 16 In addition, interferon treatment can contribute
to depression in HCV-infected patients. However, depression
can be treated and should not be a limiting factor for the treatment
of patients with HCV with peginterferon–ribavirin combination
therapy. 3
There are several theories as to what causes depression in
HCV-infected patients treated with interferon. Serotonin depletion
is one of them. Serotonin is one of the important molecules
involved in the pathogenesis of depression. Interferon-related
depression is thought to occur through serotonin depletion via
depletion of tryptophan, the substrate required for serotonin
production. Tryptophan has to compete competitively with an
active transport mechanism to get into the brain to produce
serotonin. Interferons, interleukin-2, and other cytokines deplete
the peripheral tryptophan supply, and, as a result, the brain has
less substrate to form serotonin. The selective serotonin reuptake
inhibitors (SSRIs) are often effective in treating depression
in HCV-infected patients being treated with interferon, which
supports the idea that serotonin is involved.
Class Effect
There are no data directly comparing the efficacy or side
effects of peginterferon alfa-2a and peginterferon alfa-2b that
demonstrate one induces a higher incidence of depression
than the other. Although the frequency of depression differed
between the 2 trials of peginterferon (eg, 22% in the peginterferon
alfa-2a trial and 31% in the peginterferon alfa-2b trial), 1,2
there were important differences between these trials that likely
led to this discrepancy. First, in both of these studies, the diagnosis
of depression was very subjective; no validated tools were
used. Second, in the peginterferon alfa-2a registration trials,
26% of patients discontinued therapy at 12 weeks, so only 74%
of the patients in the trial partook of the full year of therapy; this
contrasts with a 14% discontinuation rate among patients in the
peginterferon alfa-2b trial. It is likely that the rates of depression
would have been different if the entire population in the peginterferon
alfa-2a trial had been treated for the full 48 weeks. Finally,
there are geographic differences in diagnosed depression
rates. The registration study of peginterferon alfa-2b was conducted
at predominantly North American sites, whereas the
majority of sites in the peginterferon alfa-2a registration study
were European.
Treatment Options
There is emerging evidence that SSRIs may be the agents of
choice for treating interferon-associated depression in patients
with hepatitis C. 17,18 In a small study, Kraus et al treated 14
patients with HCV and depression using paroxetine 20 mg per
day. The study results found that depression scores declined in
all the patients, and 11 patients were able to complete interferon
therapy. 16
In patients with liver disease, SSRIs have been shown to be
safe and well tolerated. 19 The choice of which SSRI agent to prescribe
should be based on patient symptoms (ie, in patients with
fatigue or cognitive slowing, the more activating agents [fluoxetine
and sertraline] may be preferred to the less activating agents
[paroxetine and fluvoxamine]). 20 Other first-line antidepressants
(eg, venlafaxine, bupropion, and nefazodone) may have efficacy
similar to that of the more activating SSRIs, but they have not
been as well studied in HCV-infected patients. 15 Tricyclic antidepressants,
which have an anticholinergic effect and may cause
sedation, should be avoided in this population, particularly if pronounced
fatigue and cognitive slowing are present. 15
Hematologic Side Effects
Hematologic side effects—anemia, neutropenia, and thrombocytopenia—frequently
necessitate dosage modifications or
discontinuation in HCV-infected patients taking peginterferon–ribavirin
combination therapy, and such dose reductions
adversely affect the ability to achieve SVR. 1,2 Regardless of the
peginterferon product used, the rate of achieving SVR will
decrease by a significant 17% to 29% if the patients receive

16%
14%
12%
10%
8%
6%
14.2: 1.7 g/dL
11.2: 1.3 g/dL
EPO
SOC
4%
2%
0%
N=62
EPO
SOC
Study
Entry
34
28
Week
2
31
23
Week
4
34
21
Week
8
33
21
Week
12
29
15
Week
16
21
14
Figure 3. Pegylated interferons: anemia.
Based on references 21 and 22.
levels in this population. In one study, Dieterich and Spivak
randomly assigned 62 patients to receive either the standard of
care (dose reduction) or treatment with erythropoietin if they
became anemic (Figure 3). 21,22 Although the baseline ribavirin
doses were similar (approximately 1,000 mg per day), the mean
reduction in ribavirin dose was significantly less for the group
that received erythropoietin. In addition, there was a 3-g/dL
difference in the hemoglobin level measured at 3 months in the
group receiving erythropoietin from that of the standard-of-care
treatment group. The erythropoietin-treated patients also had
higher quality-of-life scores.
If the hemoglobin level falls below 12 g/dL and the patient
has symptoms of anemia, or if the hemoglobin level falls below
10 g/dL, once-weekly erythropoietin treatment can be beneficial.
If the patient is iron depleted, iron should be given as well.
Neutropenia
Neutropenia occurs more commonly among patients treated
with pegylated interferons than nonpegylated interferons. Granulocyte
colony–stimulating factor (G-CSF) has become widely
used in this setting to treat neutropenia and thereby reduce the
need for dose reduction and the discontinuation of antiviral
therapy. This growth factor serves to bolster neutrophil counts,
allowing higher doses of interferon to be administered. One
approach to neutropenia management in this patient population
is to institute G-CSF therapy when the absolute neutrophil
count (ANC) falls below 500/mm 3 , although some have advocated
starting at an ANC of 1,000/mm 3 . G-CSF is generally
administered at a dose of 300 mcg 1 to 3 times weekly, then
titrated to maintain an ANC above 750/mm 3 . Although the use
of this supportive agent has been shown to allow increased
interferon dosing, more studies are needed to determine
whether this translates into an increase in SVR. Importantly,
there have been no studies in this treatment population correlating
low ANC with infections.
Conclusion
In summary, advances in the treatment of HCV infection with
peginterferon–ribavirin combination therapy offer patients a
good chance of achieving an SVR, but clinicians need to closely
monitor patients for the development of side effects, particularly
depression, anemia, and neutropenia. Depression occurs
with all classes of interferon, and can be treated wirh antidepressant
agents. The development of hematologic side effects
should also be anticipated when one is treating patients with
peginterferon–ribavirin combination therapy, and managed with
available supportive agents. Careful management of these
potential side effects can improve therapeutic outcomes.
6
References
1. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus
ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment
of chronic hepatitis C: a randomised trial. Lancet. 2001;358:959-965.
2. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin
for chronic hepatitis C virus infection. N Engl J Med. 2002;347:
975-982.
3. National Institutes of Health Consensus Development Conference
Statement: Management of hepatitis C 2002. Gastroenterology. 2002;
123:2082-2099.
4. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression
in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLIN-
IVIR, and DOSVIRC groups. Lancet. 1997;349:825-832.
5. Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of
chronic hepatitis C. Hepatology. 1996;23:1334-1340.
6. Mathurin P, Moussalli J, Cadranel JF, et al. Slow progression rate of fibrosis
in hepatitis C virus patient with persistently normal alanine transaminase
activity. Hepatology. 1998;27:868-872.
7. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J.
Early virologic response to treatment with peginterferon alfa-2b plus ribavirin
in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.

References (continued)
8. Ferenci P, Fried MW, Chaneac M. A dynamic model to predict sustained
virological response to combination peginterferon alfa-2a and ribavirin
therapy in patients with chronic hepatitis C. Hepatology. 2003;38(Oct
suppl):635A. Abstract #995.
9. Buti M, Valdes A, Sanchez-Avila F, Esteban R, Lurie Y. Extending combination
therapy with peginterferon alfa-2b plus ribavirin for genotype 1
chronic hepatitis C late responders: a report of 9 cases. Hepatology.
2003;37:1226-1227.
10. Berg T, Hinrichsen H, Heintges T, et al. Comparison of 48 or 72 weeks of
treatment with peginterferon alfa-2a plus ribavirin in treatment-naïve
patients with chronic hepatitis C infected with HCV genotype 1. Hepatology.
2003;38(Oct suppl):317A. Abstract #328.
11. Poynard T, McHutchison JG, Manns MP, et al. Impact of pegylated interferon
alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis
C. Gastroenterology. 2002;122:1303-1313.
12. Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled
trial of maintenance interferon therapy for patients with chronic hepatitis C
virus and persistent viremia. Gastroenterology. 1999;117:1164-1172.
13. Afdhal NH, Freilich B, Black M, et al. Comparison of therapy with PEG-
Intron 0.5 mcg/kg versus colchicine 0.6 mg bid in 250 patients with cirrhosis
and HCV: interim data from COPILOT. Hepatology. 2002;36:312A.
14. McHutchison JG, Manns MP, Patel K, et al. Adherence to combination
therapy enhances sustained response in genotype-1–infected patients
with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.
15. Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis
C, interferon alfa, and depression. Hepatology. 2000;31:1207-1211.
16. Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M. Paroxetine for the
treatment of interferon-alpha–induced depression in chronic hepatitis C.
Aliment Pharmacol Ther. 2002;16:1091-1099.
17. Hauser P, Khosla J, Aurora H, et al. A prospective study of the incidence
and open-label treatment of interferon-induced major depressive disorder
in patients with hepatitis C. Mol Psychiatry. 2002;7:942-947.
18. Epstein SA. Psychotropic medications in gastrointestinal and hepatic disease.
Adv Psychosom Med. 1994;21:49-60.
19. Edwards JG, Anderson I. Systematic review and guide to selection of
selective serotonin reuptake inhibitors. Drugs. 1999;57:507-533.
20. Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology.
2003;124:1711-1719.
21. Dieterich DT, Spivak JL. Hematologic disorders associated with hepatitis
C virus infection and their management. Clin Infect Dis. 2003;37:533-541.
22. Dieterich DT. Once-weekly recombinant human erythropoietin (epoetin
alfa) facilitates optimal ribavirin (RBV) dosing in hepatitis C virus (HCV)-
infected patients receiving interferon alfa-2 (INF)/RBV combination therapy.
Presented at Digestive Disease Week; May 20-23, 2001; Atlanta, Ga.
Abstract #340.
CME Post-test
Select the single-letter response that best answers the question or completes the sentence.
1. All but which of the following risk factors put HCVinfected
patients at higher risk for liver fibrosis and
further progression of liver disease
a. Male sex
b. Long duration of infection
c. Hypercholesterolemia
d. History of alcoholism
2. In general, genotype 1 patients should be treated for:
a. 12 weeks
b. 24 weeks
c. 48 weeks
d. 72 weeks
3. Based on Davis et al’s evaluation of the Manns et al
data, the best definition and time point to measure
EVR are:
a. ≥1 log10 drop in viral load at 4 weeks
b. ≥1 log10 drop in viral load at 12 weeks
c. ≥2 log10 drop in viral load at 4 weeks
d. ≥2 log10 drop in viral load at 12 weeks
4. What was the negative predictive value when EVR was
defined as ≥2 log10 drop in viral load at 12 weeks
a. 0%
b. 20%
c. 50%
d. 100%
5. Evaluating the Manns et al trial data, Davis et al found
that early discontinuation or interruptions of therapy
longer than 2 weeks reduced SVR:
a. from 82% to 70%
b. from 72% to 50%
c. from 62% to 40%
d. from 45% to 25%
6. The COPILOT maintenance trial is evaluating the
efficacy of lower than standard-dose peginterferon
alfa-2b compared with:
a. calcitonin
b. colchicine
c. erythropoietin
d. G-CSF
7. Interferon-related depression is thought to occur
through serotonin depletion via depletion of:
a. vitamin A
b. vitamin B
c. dimethylglycine
d. tryptophan
8. The more activating SSRIs include:
a. fluoxetine and paroxetine
b. paroxetine and fluvoxamine
c. fluoxetine and sertraline
d. sertraline and paroxetine
9. Tricyclic antidepressants should be avoided in HCVinfected
patients with depression because of potential:
a. anticholinergic side effects
b. sexual side effects
c. cholinergic effects
d. weight gain
10. In the treatment of peginterferon-related neutropenia,
G-CSF is generally started at a dose of:
a. 300 mcg 1 to 3 times weekly
b. 300 mcg 1 to 3 times daily
c. 500 mg 1 to 3 times weekly
d. 500 mcg 1 to 3 times weekly
7

ANSWER SHEET & EVALUATION FORM
Guide to Managing Hepatitis C With Pegylated Interferons
Release Date: April 2004 Expiration Date: April 30, 2005
✄
A passing score of 70% or higher on the post-test awards the participant one (1) AMA PRA Category 1 credit. To claim
continuing education credit, individuals must complete the self-study activity, post-test and evaluation. Please submit your
answers only once through one of the methods listed below.
Mail to: Attn: Distance Education or Participate online at: Test Code: MDEMHC03
Continuing Education Office
www.gastroendonews.com
Colleges of Pharmacy and Medicine
University of Kentucky
One Quality Street, 6th Floor
Lexington, KY 40507-1428
Must be postmarked by April 30, 2005
Participant Information: (Please print)
Name:
Credentials: Soc. Sec. #:
Address:
City: State: Zip:
Daytime Phone:
Fax:
E-mail:
Signature:
1. a b c d
2. a b c d
3. a b c d
4. a b c d
5. a b c d
Post-Test Answers:
6. a b c d
7. a b c d
8. a b c d
9. a b c d
10. a b c d
Evaluation:
Ratings: 1=Poor 3=Satisfactory 5=Excellent
1. Extent to which the objectives were achieved: 1 2 3 4 5
2. Potential impact on your practice: 1 2 3 4 5
3. Detail of information presented: 1 2 3 4 5
4. Overall evaluation of this CE activity: 1 2 3 4 5
5. Suggestions for future CE topics:
SR326
8